Although many life-threatening drug reactions are reported each year, very little is known about their etiologies. We believe that many of these toxicities might be caused by the covalent alterations of specific macromolecules by reactive metabolites of drugs. These modifications might lead directly to toxicity by changing the physiological function of macromolecules or indirectly by making the macromolecules immunogenic, leading to immune-mediated toxicities. This year two new liver neoantigens associated with halothane hepatitis have been identified, a trifluoro- acetylated 58 kDa protein and a trifluoroacetylated 82 kDa protein. The 82 kDa protein corresponded to GRP78, a glucose-regulated stress protein, whereas the 58 kDa protein had high sequence homology to phosphatidylinositol-specific phospholipase C-alpha, but did not have activity. Several replacements of the ozone depleting chlorofluorocarbons are structurally similar to halothane and are metabolized analogously, raising the possibility that individuals exposed to these agents may develop allergic hepatitis. Recently, we have started to determine the targets of reactive metabolites of nonsteroidal anti-inflammatory agents, one of the most widely used classes of drugs. Although relatively safe, idiosyncratic life-threatening hepatitis, nephritis, hemolytic anemia, and agranulocytosis are produced by some of these agents. We have chosen diclofenac as a model drug to study the mechanisms of toxicities produced by this class of drugs.